The present invention relates to a method for predicting restenosis following coronary intervention by measuring a human lipocalin-type prostaglandin D synthase (hereinafter referred to as L-PGDS) concentration in a body fluid sample. More particularly, the invention relates to the method for predicting restenosis following coronary intervention using changes in the L-PGDS concentration in the sample as an indicator.
Methods for treating an ischemic heart disease such as angina, which brings about stenosis in a coronary, include pharmacotherapy, coronary artery bypass graft, and coronary intervention.
Pharmacotherapy is a basic treatment for angina, and is used for improving myocardinal ischemic conditions. Its mechanism of action works in two ways: one expands a coronary artery, improving a bloodflow into the myocardium (e.g. nitrous acid), and the other decreases the heart rate and blood pressure to reduce oxygen consumption of the myocardium, thereby preventing the occurrence of an attack (e.g. xcex2 blocker agent). On the other hand, coronary artery bypass graft is a method in which a blood vessel is newly established for a stenosed part to connect the aorta with peripheries of the stenosed part in a coronary artery, thereby reconstructing the circulation of the coronary artery.
Coronary intervention is a method in which an intravascular catheter is inserted into a femoral artery and directed to a stenosed part, and then a physical treatment is performed locally to ensure blood flow. Various devices are used in coronary intervention. A Percutaneous Transluminal Coronary Angioplasty (referred to as PTCA hereinafter) is a method in which a balloon catheter is inserted into a blood vessel and expanded in a stenosed part, thereby enlarging the stenosed part to recover a normal bloodflow. A coronary stent implantation is a method in which a metal wire-woven tube is implanted in a stenosed part using a catheter to support a lumen of the coronary artery, thereby ensuring a normal bloodflow.
As described above, coronary intervention is not accompanied by a surgical operation such as thoracotomy. Therefore, ever since Gruentig performed the first successful PTCA in 1977, it has become widely used in Japan, not to mention Europe and America. In the early days, the application of coronary intervention was limited to stable angina with a restricted lesion in a single vessel. Its application was then extended to a stable angina with lesions in multiple vessels, and further, to an angina with a complete obstruction. Nowadays, it has become one of the established treatments for ischemic heart diseases. However, there is a significant weak point in PTCA in that an acute and subacute thrombotic occlusion occurs in an early stage following the operation, and that restenosis occurs within 3 to 4 months at 30-40% probability (Nobuyoshi, M. et al. (1988) Am. Coll. Cardiol. 12: 616-623).
Among these, for the acute and subacute thrombotic occlusion which occurs at an early stage, a method in which an intracoronary stent is used as a device, and in addition, aspirin and ticlopidine are used together, has been established as a typical prevention (Lincoff, A. M. et al. (1993) J. Am. Coll. Cardiol. 21: 866-875).
On the other hand, a step towards solving the restenosis problem was also presented by the development of the intracoronary stent. The restenosis occurrence following intervention in cases where this device is used decreased to 20-30% compared to PTCA using a balloon. Later on, the advent of various stents greatly lowered the probability of restenosis, however, they have fallen short of completely preventing restenosis (Fishman, D. L. et al. (1994) N. Engl. J. Med. 331: 496-501; Serruys, P. W. et al. (1994) N. Engl. J. Med. 331: 489-501).
Therefore, together with the improvement of such devices, prevention by medication has also been attempted.
Since the restenosis is triggered by platelets accumulating toward an intimal injury caused by coronary intervention as well as the growth of a newly-born intima, and by a platelet-derived growth factor being produced, the effect of antiplatelets was expected. However, none of aspirin, dipyridamole, and ticlopidine could reduce the restenosis occurrence. Furthermore, trapidil, which is an antagonist of the platelet-derived growth factor, was of no effect, and the preventive efficacy of anticoagulants, heparin and warfarin, was not confirmed either. Still further, it was reported that the restenosis rate is higher in the case of coronary spastic angina, and in view of the cause-effect relationship between restenosis and coronary spastic angina, the effect of a calcium antagonist was prospected. However, neither diltiazem nor nifedipine was effective (Arteriosclerosis: 122; Medical Aoi Press).
Under such circumstances, drugs that are being recognized as effective for restenosis have recently appeared. It has been reported that drugs that were prescribed as a keloidal drug such as tranilast which is an antiallergic agent and cilostazol which is an antiplatelet agent showed favorable results after PTCA, and basic research concerning these drugs is now proceeding (Ishiwata (1996) Kowa medical report Vol. 39, No. 3: 127-33; Tamal H. et al. (1994) Circulation 90: I-652; Katsuki et al. (1998) Medicina 35: 659-661). Although neither drug has been clinically tested on a large-scale yet, it is considered certain that effective drugs including these will emerge in the future.
Thus, an early prediction of the occurrence of restenosis will enable an effective precaution to be taken using drugs. Therefore, a method for early prediction of occurrence of restenosis following coronary intervention has been long expected, however, early prediction is not easy since restenosis following the intervention often occurs asymptomatically.
Nowadays, various factors involved in restenosis are being studied, and their relationship with the mechanism of restenosis is being examined. Since the plasma concentration of angiotensin converting enzyme is correlated with the amount of intimal growth following a stent placement, its potential as an indicator for predicting restenosis has been suggested (Ohishi (1995) Hypertension 26: 561). Furthermore, based on the assumption that a constrictive remodeling is involved in occurrence of restenosis following PTCA, studies on endothelin (referred to as ET hereinafter) which is a vasoactive substance having a strong vasoconstrictive effect, have been carried out. Doi et al. measured the ET concentration in a coronary artery before/after/three months after PTCA, and reported that a group with significant stenosis showed a greater degree of changes in the concentration compared to a group without significant stenosis was not confirmed, and they reported clinical data indicating that the ET increase in the coronary circulation played an important role in the mechanism of coronary artery restenosis following PTCA (Journal of Cardiology vol. 32 Supplement 1: p391). It is suggested that the platelet-derived growth factor also has a potential as a factor for predicting restenosis in view of its involvement in a restoration process after being damaged by PTCA (Haneo et al. (1993) Journal of Clinical and Experimental Medicine 167 No. 6 p512). Naruko et al. carried out an investigation on the expression of natriuretic peptide system in a restenosed part, and confirmed the expression of natriuretic peptide C, natriuretic peptide A receptor, and natriuretic peptide clearance receptor in a newly-born intima of the restenosed part (Journal of Japan Atherosclerosis society vol. 25 Supplement 1998: 140).
However, for each agent excepting ET, the data merely indicates its involvement in the mechanism of restenosis, and no clinical findings capable of predicting restenosis at an early stage after coronary intervention have been obtained so far. Additionally, since ET requires a long-term follow-up of the changes in the concentration, it is not practical from the viewpoint of early prediction under present circumstances.
Furthermore, several investigations have also been carried out on a method for predicting restenosis using an apparatus. Among the dynamics of coronary circulation during PTCA, a collateral blood flow ratio at the time of coronary occlusion [(QC/QN) max=coronary artery wedge pressure/average arterial pressure], that is to say, a collateral circulation upon coronary occlusion with balloon expansion during PTCA, was measured upon completion of PTCA, and its relationship with subsequently occuring restenosis was examined. As a result, it is reported that the degree of (QC/QN) max and restenosis are closely related (Journal of Cardiology vol. 32 Supplement I: P393).
Kikuchi et al. showed that the transition of QTd and QTcd before coronary intervention, on the day following the intervention, in the period immediately after the intervention (5-24 days), and in the chronic period (69-204 days) using a 12 inducible electrocardiogram in the resting state after the intervention can be used as an indicator for predicting restenosis (Journal of Cardiology vol. 32 Supplement I: p394).
However, these methods are not suitable for an early prediction since, on the one hand, (QC/QN) max is invasive because it is accompanied by an intracardiac catheter method, while on the other hand, the transition of QTd and QTcd requires a considerable period of time for measurement.
As mentioned above, although various investigations on a method for predicting restenosis following coronary intervention simply, non-invasively and promptly have been carried out, an outstanding predicting method that overcomes these problems has not been reported yet.
On the other hand, we found that it is possible to detect and predict ischemic diseases using a L-PGDS concentration as an indicator since the L-PGDS concentration in a great cardiac vein and peripheral bloods of an angina patient is significantly higher than that of a healthy person. Further, it is possible to manage a prognosis of angina following PTCA, that is, to judge whether the stenosis is preferably eliminated by PTCA or not, since the L-PGDS concentration in great cardiac vein blood after PTCA decreases to the level of a healthy person at the convalescence stage (wo98/49559). However, its relevance with restenosis following coronary intervention has been unexamined.
The object of the present invention is to provide a method for predicting the restenosis which may occur after coronary intervention simply, non-invasively, and promptly, the method being outstanding in that no burden is placed on a patient having difficulties in a coronary angiography such as an elderly person, kidney-diseased patient, etc.
To solve the above problems, we studied extensively and intensively as to whether a L-PGDS concentration can be a factor for predicting restenosis. Specifically, the L-PGDS concentration in a body fluid sample following coronary intervention was traced and its relevance with restenosis was examined. As a result, serial changes in the L-PGDS concentration in the sample after the intervention or changes before/after the intervention were divided into 2 types: 1) Type where the concentration decreased once after the intervention, then subsequently increased up until 48 hours after the intervention; 2) Type where the concentration decreased once after the intervention, and subsequently showed almost no change up until 48 hours after the intervention. It was found that this type-division could be used to classify patients into those in which restenosis would occur later and those in which no restenosis would occur. That is to say, it was elucidated that restenosis occurs a few months later in the case where no increase in the L-PGDS concentration in a body fluid sample has been observed at an early stage after the intervention, while on the other hand, no restenosis occurs in the case where the increase in the L-PGDS concentration has been observed. Accordingly, tracing the serial changes in the L-PGDS concentration in a body fluid sample enabled the prediction of the occurrence of restenosis following coronary intervention.
Thus, the present invention provides a method for predicting restenosis following coronary intervention wherein the L-PGDS concentration in a body fluid sample is measured after the intervention, or before and after the intervention, and the changes in its value are used as an indicator, the method providing the following items (1)-(7):
(1) A method for predicting restenosis following coronary intervention by measuring a L-PGDS concentration in a body fluid sample;
(2) The method of the above (1) wherein a serial change in the L-PGDS concentration in the body fluid sample after coronary intervention is used as an indicator;
(3) The method of the above (1) wherein a change in the L-PGDS concentration in the body fluid sample between before and after coronary intervention is used as an indicator;
(4) The method of the above (1) wherein the L-PGDS concentration in the body fluid sample is measured using an immunological measuring method;
(5) The method of the above (1) wherein the body fluid sample is blood or urine;
(6) The method of the above (5) wherein the body fluid sample is blood taken from a coronary or peripheral blood; and
(7) The method of the above (1) wherein coronary intervention is percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy (DCA), transluminal extraction catheter (TEC), rotary atherectomy coronary angioplasty (Rotablator), excimer laser coronary angioplasty, or intracoronary stenting.
The specification of the present invention includes part or all of the contents as described in the specification and/or drawings of Japanese Patent Application No. 11-51216, which is a priority document of the present application.